Division of Tumor Biology and Immunology, the Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands.
Division of Molecular Genetics, the Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands.
Cell Rep. 2020 Dec 29;33(13):108533. doi: 10.1016/j.celrep.2020.108533.
Altering ubiquitination by disruption of deubiquitinating enzymes (DUBs) affects hematopoietic stem cell (HSC) maintenance. However, comprehensive knowledge of DUB function during hematopoiesis in vivo is lacking. Here, we systematically inactivate DUBs in mouse hematopoietic progenitors using in vivo small hairpin RNA (shRNA) screens. We find that multiple DUBs may be individually required for hematopoiesis and identify ubiquitin-specific protease 15 (USP15) as essential for HSC maintenance in vitro and in transplantations and Usp15 knockout (KO) mice in vivo. USP15 is highly expressed in human hematopoietic tissues and leukemias. USP15 depletion in murine progenitors and leukemia cells impairs in vitro expansion and increases genotoxic stress. In leukemia cells, USP15 interacts with and stabilizes FUS (fused in sarcoma), a known DNA repair factor, directly linking USP15 to the DNA damage response (DDR). Our study underscores the importance of DUBs in preserving normal hematopoiesis and uncovers USP15 as a critical DUB in safeguarding genome integrity in HSCs and leukemia cells.
通过破坏去泛素化酶（DUBs）来改变泛素化会影响造血干细胞（HSC）的维持。然而，体内造血过程中 DUB 功能的综合知识仍然缺乏。在这里，我们使用体内短发夹 RNA（shRNA）筛选系统地在小鼠造血祖细胞中失活 DUB。我们发现多个 DUB 可能单独需要造血，并确定泛素特异性蛋白酶 15（USP15）在体外和移植中维持 HSC 以及体内 Usp15 敲除（KO）小鼠中是必需的。USP15 在人类造血组织和白血病中高度表达。在小鼠祖细胞和白血病细胞中耗尽 USP15 会损害体外扩增并增加遗传毒性应激。在白血病细胞中，USP15 与肉瘤融合（FUS）相互作用并稳定 FUS（一种已知的 DNA 修复因子），直接将 USP15 与 DNA 损伤反应（DDR）联系起来。我们的研究强调了 DUB 在维持正常造血中的重要性，并揭示了 USP15 作为保护 HSC 和白血病细胞基因组完整性的关键 DUB 的重要性。
